A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse
0301 basic medicine
Proline
Molecular Sequence Data
TRPM Cation Channels
Apoptosis
Protein Structure, Secondary
Cell Line
Protein Structure, Tertiary
Mice
03 medical and health sciences
Transient Receptor Potential Channels
Amino Acid Substitution
Animals
Amino Acid Sequence
Hearing Loss
DOI:
10.1073/pnas.0709846104
Publication Date:
2007-11-29T01:45:29Z
AUTHORS (8)
ABSTRACT
Homozygote varitint-waddler (Va) mice, expressing a mutant isoform (A419P) of TRPML3 (mucolipin 3), are profoundly deaf and display vestibular pigmentation deficiencies, sterility, perinatal lethality. Here we show that the carrying an A419P mutation represents constitutively active cation channel can also be identified in native hair cells as distinct inwardly rectifying current. We hypothesize constitutive activation occurs result helix-breaking proline substitution transmembrane-spanning domain 5 (TM5). A scan demonstrated inner third TRPML3's TM5 is highly susceptible to proline-based kinks. Proline substitutions other TRP channels revealed TRPML1, TRPML2, TRPV5, TRPV6 similar susceptibility at comparable positions, whereas were not affected. conclude molecular basis for deafness mouse cell death caused by activity. To our knowledge, study provides first direct mechanistic link ion with mammalian hearing loss.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (35)
CITATIONS (139)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....